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Rho GTPases: functions and association with cancer

Clinical & Experimental Metastasis volume 24, pages 657–672 (2007)Cite this article

Abstract

Rho GTPases are small proteins that act as binary molecular switches in a wide range of signalling pathways upon stimulation of cell surface receptors. Three different classes of regulatory proteins control their activity. In the activated state small GTPases are able to bind a variety of effector proteins and initiate downstream signalling. Rho GTPases regulate important cellular processes ranging from cytoskeletal remodelling and gene expression to cell proliferation and membrane trafficking. Therefore it is not surprising that deregulated Rho signalling can contribute to disturbed cellular phenotypes in a wide range of diseases. The main focus of this review will be the diversity of functions of Rho GTPases and the effects of aberrant Rho GTPase signalling in various aspects of cancer.

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Abbreviations

AJ:

Adherens junction

Arp:

Actin-related protein

DH:

Dbl homology

DOCK:

Dedicator of cytokinesis

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

GAP:

GTPase-activating protein

GDI:

Guanine nucleotide dissociation inhibitor

GEF:

Guanine nucleotide exchange factor

MMP:

Matrix metalloproteinase

NFκB:

Nuclear factor κB

N-WASP:

Neural Wiskott-Aldrich-syndrome protein

PAK:

p21-activated kinase

PH:

Pleckstrin homology

PKC:

Protein kinase C

ROCK:

Rho-associated coiled-coil containing protein kinase

ROS:

Reactive oxygen species

SRF:

Serum response factor

Tiam1:

T-lymphoma invasion and metastasis 1

TJ:

Tight junction

WAVE:

WASP-like verprolin-homologous protein

References

  1. Bar-Sagi D, Hall A (2000) Ras and Rho GTPases: a family reunion. Cell 103:227–238

    PubMed  CAS  Article  Google Scholar 

  2. Mitin N, Rossman KL, Der CJ (2005) Signaling interplay in Ras superfamily function. Curr Biol 15:R563–R574

    PubMed  CAS  Article  Google Scholar 

  3. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247–269

    PubMed  CAS  Article  Google Scholar 

  4. Buchsbaum RJ (2007) Rho activation at a glance. J Cell Sci 120:1149–1152

    PubMed  CAS  Article  Google Scholar 

  5. Juliano RL (2002) Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu Rev Pharmacol Toxicol 42:283–323

    PubMed  CAS  Article  Google Scholar 

  6. Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118:843–846

    PubMed  CAS  Article  Google Scholar 

  7. Valencia A, Chardin P, Wittinghofer A, Sander C (1991) The ras protein family: evolutionary tree and role of conserved amino acids. Biochemistry 30:4637–4648

    PubMed  CAS  Article  Google Scholar 

  8. Aspenstrom P, Ruusala A, Pacholsky D (2007) Taking Rho GTPases to the next level: the cellular functions of atypical Rho GTPases. Exp Cell Res 313:3673–3679

    PubMed  Article  CAS  Google Scholar 

  9. Fransson S, Ruusala A, Aspenstrom P (2006) The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. Biochem Biophys Res Commun 344:500–510

    PubMed  CAS  Article  Google Scholar 

  10. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635

    PubMed  CAS  Article  Google Scholar 

  11. Ridley AJ (2001) Rho family proteins: coordinating cell responses. Trends Cell Biol 11:471–477

    PubMed  CAS  Article  Google Scholar 

  12. van Aelst L, D’Souza-Schorey C (1997) Rho GTPases and signaling networks. Genes Dev 11:2295–2322

    PubMed  Article  Google Scholar 

  13. Schmidt A, Hall A (2002) Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev 16:1587–1609

    PubMed  CAS  Article  Google Scholar 

  14. Mertens AE, Roovers RC, Collard JG (2003) Regulation of Tiam1-Rac signalling. FEBS Lett 546:11–16

    PubMed  CAS  Article  Google Scholar 

  15. Rossman KL, Der CJ, Sondek J (2005) GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6:167–180

    PubMed  CAS  Article  Google Scholar 

  16. Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS (2002) Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat Cell Biol 4:574–582

    PubMed  CAS  Google Scholar 

  17. Cote JF, Vuori K (2007) GEF what? Dock180 and related proteins help Rac to polarize cells in new ways. Trends Cell Biol 17:383–393

    PubMed  CAS  Article  Google Scholar 

  18. Meller N, Merlot S, Guda C (2005) CZH proteins: a new family of Rho-GEFs. J Cell Sci 118:4937–4946

    PubMed  CAS  Article  Google Scholar 

  19. van Horck FP, Ahmadian MR, Haeusler LC, Moolenaar WH, Kranenburg O (2001) Characterization of p190RhoGEF, a RhoA-specific guanine nucleotide exchange factor that interacts with microtubules. J Biol Chem 276:4948–4956

    PubMed  Article  Google Scholar 

  20. Salazar MA, Kwiatkowski AV, Pellegrini L, Cestra G, Butler MH, Rossman KL, Serna DM, Sondek J, Gertler FB, De Camilli P (2003) Tuba, a novel protein containing bin/amphiphysin/Rvs and Dbl homology domains, links dynamin to regulation of the actin cytoskeleton. J Biol Chem 278:49031–49043

    PubMed  CAS  Article  Google Scholar 

  21. Bellanger JM, Estrach S, Schmidt S, Briancon-Marjollet A, Zugasti O, Fromont S, Debant A (2003) Different regulation of the Trio Dbl-Homology domains by their associated PH domains. Biol Cell 95:625–634

    PubMed  CAS  Article  Google Scholar 

  22. Movilla N, Dosil M, Zheng Y, Bustelo XR (2001) How Vav proteins discriminate the GTPases Rac1 and RhoA from Cdc42. Oncogene 20:8057–8065

    PubMed  CAS  Article  Google Scholar 

  23. Abe K, Rossman KL, Liu B, Ritola KD, Chiang D, Campbell SL, Burridge K, Der CJ (2000) Vav2 is an activator of Cdc42, Rac1, and RhoA. J Biol Chem 275:10141–10149

    PubMed  CAS  Article  Google Scholar 

  24. Moon SY, Zheng Y (2003) Rho GTPase-activating proteins in cell regulation. Trends Cell Biol 13:13–22

    PubMed  CAS  Article  Google Scholar 

  25. Tcherkezian J, Lamarche-Vane N (2007) Current knowledge of the large RhoGAP family of proteins. Biol Cell 99:67–86

    PubMed  CAS  Article  Google Scholar 

  26. Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129:865–877

    PubMed  CAS  Article  Google Scholar 

  27. Wildenberg GA, Dohn MR, Carnahan RH, Davis MA, Lobdell NA, Settleman J, Reynolds AB (2006) p120-catenin and p190RhoGAP regulate cell–cell adhesion by coordinating antagonism between Rac and Rho. Cell 127:1027–1039

    PubMed  CAS  Article  Google Scholar 

  28. Nimnual AS, Taylor LJ, Bar-Sagi D (2003) Redox-dependent downregulation of Rho by Rac. Nat Cell Biol 5:236–241

    PubMed  CAS  Article  Google Scholar 

  29. Wherlock M, Mellor H (2002) The Rho GTPase family: a Racs to Wrchs story. J Cell Sci 115:239–240

    PubMed  CAS  Google Scholar 

  30. DerMardirossian C, Bokoch GM (2005) GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol 15:356–363

    PubMed  CAS  Article  Google Scholar 

  31. Ridley AJ (2006) Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 16:522–529

    PubMed  CAS  Article  Google Scholar 

  32. Robbe K, Otto-Bruc A, Chardin P, Antonny B (2003) Dissociation of GDP dissociation inhibitor and membrane translocation are required for efficient activation of Rac by the Dbl homology-pleckstrin homology region of Tiam. J Biol Chem 278:4756–4762

    PubMed  CAS  Article  Google Scholar 

  33. Price LS, Langeslag M, ten Klooster JP, Hordijk PL, Jalink K, Collard JG (2003) Calcium signaling regulates translocation and activation of Rac. J Biol Chem 278:39413–39421

    PubMed  CAS  Article  Google Scholar 

  34. Bishop AL, Hall A (2000) Rho GTPases and their effector proteins. Biochem J 348(Pt 2):241–255

    PubMed  CAS  Article  Google Scholar 

  35. Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 29:356–370

    PubMed  CAS  Article  Google Scholar 

  36. Hofmann C, Shepelev M, Chernoff J (2004) The genetics of Pak. J Cell Sci 117:4343–4354

    PubMed  CAS  Article  Google Scholar 

  37. Riento K, Ridley AJ (2003) Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 4:446–456

    PubMed  CAS  Article  Google Scholar 

  38. Croft DR, Olson MF (2006) The Rho GTPase effector ROCK regulates cyclin A, cyclin D1, and p27Kip1 levels by distinct mechanisms. Mol Cell Biol 26:4612–4627

    PubMed  CAS  Article  Google Scholar 

  39. Rohatgi R, Ma L, Miki H, Lopez M, Kirchhausen T, Takenawa T, Kirschner MW (1999) The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 97:221–231

    PubMed  CAS  Article  Google Scholar 

  40. Qiu RG, Chen J, Kirn D, McCormick F, Symons M (1995) An essential role for Rac in Ras transformation. Nature 374:457–459

    PubMed  CAS  Article  Google Scholar 

  41. Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J, Collard JG, Der CJ (2002) Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat Cell Biol 4:621–625

    PubMed  CAS  Google Scholar 

  42. Sander EE, ten Klooster JP, van DS, van der Kammen RA, Collard JG (1999) Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol 147:1009–1022

    PubMed  CAS  Article  Google Scholar 

  43. Zondag GC, Evers EE, ten Klooster JP, Janssen L, van der Kammen RA, Collard JG (2000) Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J Cell Biol 149:775–782

    PubMed  CAS  Article  Google Scholar 

  44. Aspenstrom P, Fransson A, Saras J (2004) Rho GTPases have diverse effects on the organization of the actin filament system. Biochem J 377:327–337

    PubMed  Article  Google Scholar 

  45. Fransson A, Ruusala A, Aspenstrom P (2003) Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J Biol Chem 278:6495–6502

    PubMed  CAS  Article  Google Scholar 

  46. Hall A (2005) Rho GTPases and the control of cell behaviour. Biochem Soc Trans 33:891–895

    PubMed  CAS  Article  Google Scholar 

  47. Gupton SL, Eisenmann K, Alberts AS, Waterman-Storer CM (2007) mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration. J Cell Sci 120:3475–3487

    PubMed  CAS  Article  Google Scholar 

  48. Hotulainen P, Lappalainen P (2006) Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J Cell Biol 173:383–394

    PubMed  CAS  Article  Google Scholar 

  49. Machesky LM, Insall RH (1998) Scar1 and the related Wiskott-Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex. Curr Biol 8:1347–1356

    PubMed  CAS  Article  Google Scholar 

  50. Miki H, Yamaguchi H, Suetsugu S, Takenawa T (2000) IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 408:732–735

    PubMed  CAS  Article  Google Scholar 

  51. ten Klooster JP, Evers EE, Janssen L, Machesky LM, Michiels F, Hordijk P, Collard JG (2006) Interaction between Tiam1 and the Arp2/3 complex links activation of Rac to actin polymerization. Biochem J 397:39–45

    PubMed  Article  Google Scholar 

  52. Connolly BA, Rice J, Feig LA, Buchsbaum RJ (2005) Tiam1-IRSp53 complex formation directs specificity of rac-mediated actin cytoskeleton regulation. Mol Cell Biol 25:4602–4614

    PubMed  CAS  Article  Google Scholar 

  53. Palazzo AF, Cook TA, Alberts AS, Gundersen GG (2001) mDia mediates Rho-regulated formation and orientation of stable microtubules. Nat Cell Biol 3:723–729

    PubMed  CAS  Article  Google Scholar 

  54. Yamana N, Arakawa Y, Nishino T, Kurokawa K, Tanji M, Itoh RE, Monypenny J, Ishizaki T, Bito H, Nozaki K et al (2006) The Rho-mDia1 pathway regulates cell polarity and focal adhesion turnover in migrating cells through mobilizing Apc and c-Src. Mol Cell Biol 26:6844–6858

    PubMed  CAS  Article  Google Scholar 

  55. Daub H, Gevaert K, Vandekerckhove J, Sobel A, Hall A (2001) Rac/Cdc42 and p65PAK regulate the microtubule-destabilizing protein stathmin through phosphorylation at serine 16. J Biol Chem 276:1677–1680

    PubMed  CAS  Article  Google Scholar 

  56. Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S, Matsuura Y, Iwamatsu A, Perez F, Kaibuchi K (2002) Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell 109:873–885

    PubMed  CAS  Article  Google Scholar 

  57. Etienne-Manneville S (2004) Cdc42—the centre of polarity. J Cell Sci 117:1291–1300

    PubMed  CAS  Article  Google Scholar 

  58. Pegtel DM, Ellenbroek SI, Mertens AE, van der Kammen RA, de Rooij J, Collard JG (2007) The Par-Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front-rear polarity. Curr Biol 17:1623–1634

    PubMed  CAS  Article  Google Scholar 

  59. Halbleib JM, Nelson WJ (2006) Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev 20:3199–3214

    PubMed  CAS  Article  Google Scholar 

  60. Braga VM (2002) Cell–cell adhesion and signalling. Curr Opin Cell Biol 14:546–556

    PubMed  CAS  Article  Google Scholar 

  61. Fukata M, Kaibuchi K (2001) Rho-family GTPases in cadherin-mediated cell–cell adhesion. Nat Rev Mol Cell Biol 2:887–897

    PubMed  CAS  Article  Google Scholar 

  62. Mertens AE, Pegtel DM, Collard JG (2006) Tiam1 takes PARt in cell polarity. Trends Cell Biol 16:308–316

    PubMed  CAS  Article  Google Scholar 

  63. Braga VM, Betson M, Li X, Lamarche-Vane N (2000) Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell–cell adhesion in normal human keratinocytes. Mol Biol Cell 11:3703–3721

    PubMed  CAS  Google Scholar 

  64. Malliri A, van ES, Huveneers S, Collard JG (2004) The Rac exchange factor Tiam1 is required for the establishment and maintenance of cadherin-based adhesions. J Biol Chem 279:30092–30098

    PubMed  CAS  Article  Google Scholar 

  65. Sahai E, Marshall CJ (2002) ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol 4:408–415

    PubMed  CAS  Article  Google Scholar 

  66. Mertens AE, Rygiel TP, Olivo C, van der KR, Collard JG (2005) The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex. J Cell Biol 170:1029–1037

    PubMed  CAS  Article  Google Scholar 

  67. Gerard A, Mertens AE, van der Kammen RA, Collard JG (2007) The Par polarity complex regulates Rap1- and chemokine-induced T cell polarization. J Cell Biol 176:863–875

    PubMed  CAS  Article  Google Scholar 

  68. Sun CX, Downey GP, Zhu F, Koh AL, Thang H, Glogauer M (2004) Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 104:3758–3765

    PubMed  CAS  Article  Google Scholar 

  69. Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, Jasti AC, Harris CE, Lee AW, Prabhakar R, Atkinson SJ et al (2003) Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302:445–449

    PubMed  CAS  Article  Google Scholar 

  70. Nishimura T, Yamaguchi T, Kato K, Yoshizawa M, Nabeshima Y, Ohno S, Hoshino M, Kaibuchi K (2005) PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol 7:270–277

    PubMed  CAS  Article  Google Scholar 

  71. Hoppe AD, Swanson JA (2004) Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol Biol Cell 15:3509–3519

    PubMed  CAS  Article  Google Scholar 

  72. Symons M, Rusk N (2003) Control of vesicular trafficking by Rho GTPases. Curr Biol 13:R409–R418

    PubMed  CAS  Article  Google Scholar 

  73. Miralles F, Posern G, Zaromytidou AI, Treisman R (2003) Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 113:329–342

    PubMed  CAS  Article  Google Scholar 

  74. Olson MF, Ashworth A, Hall A (1995) An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science 269:1270–1272

    PubMed  CAS  Article  Google Scholar 

  75. Welsh CF (2004) Rho GTPases as key transducers of proliferative signals in g1 cell cycle regulation. Breast Cancer Res Treat 84:33–42

    PubMed  CAS  Article  Google Scholar 

  76. Schmitz AA, Govek EE, Bottner B, Van AL (2000) Rho GTPases: signaling, migration, and invasion. Exp Cell Res 261:1–12

    PubMed  CAS  Article  Google Scholar 

  77. Friedland JC, Lakins JN, Kazanietz MG, Chernoff J, Boettiger D, Weaver VM (2007) α6β4 integrin activates Rac-dependent p21-activated kinase 1 to drive NF-κB-dependent resistance to apoptosis in 3D mammary acini. J Cell Sci 120:3700–3712

    PubMed  CAS  Article  Google Scholar 

  78. Perona R, Montaner S, Saniger L, Sanchez-Perez I, Bravo R, Lacal JC (1997) Activation of the nuclear factor-kappaB by Rho, CDC42, and Rac-1 proteins. Genes Dev 11:463–475

    PubMed  CAS  Article  Google Scholar 

  79. Murga C, Zohar M, Teramoto H, Gutkind JS (2002) Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappaB. Oncogene 21:207–216

    PubMed  CAS  Article  Google Scholar 

  80. Collins T, Stone JR, Williams AJ (2001) All in the family: the BTB/POZ, KRAB, and SCAN domains. Mol Cell Biol 21:3609–3615

    PubMed  CAS  Article  Google Scholar 

  81. Wilkins A, Ping Q, Carpenter CL (2004) RhoBTB2 is a substrate of the mammalian Cul3 ubiquitin ligase complex. Genes Dev 18:856–861

    PubMed  CAS  Article  Google Scholar 

  82. Sugihara K, Nakatsuji N, Nakamura K, Nakao K, Hashimoto R, Otani H, Sakagami H, Kondo H, Nozawa S, Aiba A et al (1998) Rac1 is required for the formation of three germ layers during gastrulation. Oncogene 17:3427–3433

    PubMed  CAS  Article  Google Scholar 

  83. Chen F, Ma L, Parrini MC, Mao X, Lopez M, Wu C, Marks PW, Davidson L, Kwiatkowski DJ, Kirchhausen T et al (2000) Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability. Curr Biol 10:758–765

    PubMed  CAS  Article  Google Scholar 

  84. Boettner B, Van AL (2002) The role of Rho GTPases in disease development. Gene 286:155–174

    PubMed  CAS  Article  Google Scholar 

  85. Sahai E, Marshall CJ (2002) RHO-GTPases and cancer. Nat Rev Cancer 2:133–142

    PubMed  Article  Google Scholar 

  86. Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689

    PubMed  CAS  Google Scholar 

  87. Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308

    PubMed  CAS  Article  Google Scholar 

  88. Preudhomme C, Roumier C, Hildebrand MP, lery-Prudhomme E, Lantoine D, Lai JL, Daudignon A, Adenis C, Bauters F, Fenaux P et al (2000) Nonrandom 4p13 rearrangements of the RhoH/TTF gene, encoding a GTP-binding protein, in non-Hodgkin’s lymphoma and multiple myeloma. Oncogene 19:2023–2032

    PubMed  CAS  Article  Google Scholar 

  89. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Kuppers R, la-Favera R (2001) Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412:341–346

    PubMed  CAS  Article  Google Scholar 

  90. Fritz G, Just I, Kaina B (1999) Rho GTPases are over-expressed in human tumors. Int J Cancer 81:682–687

    PubMed  CAS  Article  Google Scholar 

  91. Fritz G, Brachetti C, Bahlmann F, Schmidt M, Kaina B (2002) Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters. Br J Cancer 87:635–644

    PubMed  CAS  Article  Google Scholar 

  92. Pan Y, Bi F, Liu N, Xue Y, Yao X, Zheng Y, Fan D (2004) Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun 315:686–691

    PubMed  CAS  Article  Google Scholar 

  93. Abraham MT, Kuriakose MA, Sacks PG, Yee H, Chiriboga L, Bearer EL, Delacure MD (2001) Motility-related proteins as markers for head and neck squamous cell cancer. Laryngoscope 111:1285–1289

    PubMed  CAS  Article  Google Scholar 

  94. Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H (2003) Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res 9:2632–2641

    PubMed  CAS  Google Scholar 

  95. Kamai T, Yamanishi T, Shirataki H, Takagi K, Asami H, Ito Y, Yoshida K (2004) Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Clin Cancer Res 10:4799–4805

    PubMed  CAS  Article  Google Scholar 

  96. Yoshioka K, Nakamori S, Itoh K (1999) Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. Cancer Res 59:2004–2010

    PubMed  CAS  Google Scholar 

  97. Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E (2000) Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19:3013–3020

    PubMed  CAS  Article  Google Scholar 

  98. Matos P, Collard JG, Jordan P (2003) Tumor-related alternatively spliced Rac1b is not regulated by Rho-GDP dissociation inhibitors and exhibits selective downstream signaling. J Biol Chem 278:50442–50448

    PubMed  CAS  Article  Google Scholar 

  99. Jordan P, Brazao R, Boavida MG, Gespach C, Chastre E (1999) Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. Oncogene 18:6835–6839

    PubMed  CAS  Article  Google Scholar 

  100. Singh A, Karnoub AE, Palmby TR, Lengyel E, Sondek J, Der CJ (2004) Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene 23:9369–9380

    PubMed  CAS  Article  Google Scholar 

  101. Matos P, Jordan P (2005) Expression of Rac1b stimulates NF-kappaB-mediated cell survival and G1/S progression. Exp Cell Res 305:292–299

    PubMed  CAS  Article  Google Scholar 

  102. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA et al (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123–127

    PubMed  CAS  Article  Google Scholar 

  103. Corbetta S, Gualdoni S, Albertinazzi C, Paris S, Croci L, Consalez GG, de C I (2005). Generation and characterization of Rac3 knockout mice. Mol Cell Biol 25:5763–5776

  104. Cho YJ, Zhang B, Kaartinen V, Haataja L, de Curtis I, Groffen J, Heisterkamp N (2005) Generation of rac3 null mutant mice: role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia. Mol Cell Biol 25:5777–5785

    PubMed  CAS  Article  Google Scholar 

  105. Mira JP, Benard V, Groffen J, Sanders LC, Knaus UG (2000) Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway. Proc Natl Acad Sci USA 97:185–189

    PubMed  CAS  Article  Google Scholar 

  106. Hordijk PL, ten Klooster JP, van der Kammen RA, Michiels F, Oomen LC, Collard JG (1997) Inhibition of invasion of epithelial cells by Tiam1-Rac signaling. Science 278:1464–1466

    PubMed  CAS  Article  Google Scholar 

  107. Malliri A, van der Kammen RA, Clark K, van dV, Michiels F, Collard JG (2002) Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417:867–871

    PubMed  CAS  Article  Google Scholar 

  108. Malliri A, Rygiel TP, van der Kammen RA, Song JY, Engers R, Hurlstone AF, Clevers H, Collard JG (2006) The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development. J Biol Chem 281:543–548

    PubMed  CAS  Article  Google Scholar 

  109. Engers R, Zwaka TP, Gohr L, Weber A, Gerharz CD, Gabbert HE (2000) Tiam1 mutations in human renal-cell carcinomas. Int J Cancer 88:369–376

    PubMed  CAS  Article  Google Scholar 

  110. Engers R, Mueller M, Walter A, Collard JG, Willers R, Gabbert HE (2006) Prognostic relevance of Tiam1 protein expression in prostate carcinomas. Br J Cancer 95:1081–1086

    PubMed  CAS  Article  Google Scholar 

  111. Adam L, Vadlamudi RK, McCrea P, Kumar R (2001) Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/beta-catenin nuclear signaling in breast cancer cells by modulating the intercellular stability. J Biol Chem 276:28443–28450

    PubMed  CAS  Article  Google Scholar 

  112. Minard ME, Kim LS, Price JE, Gallick GE (2004) The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. Breast Cancer Res Treat 84:21–32

    PubMed  CAS  Article  Google Scholar 

  113. Jarzynka MJ, Hu B, Hui KM, Bar-Joseph I, Gu W, Hirose T, Haney LB, Ravichandran KS, Nishikawa R, Cheng SY (2007) ELMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion. Cancer Res 67:7203–7211

    PubMed  CAS  Article  Google Scholar 

  114. Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, Theil KS, Krahe R, Ruutu T, Knuutila S, Bloomfield CD et al (2000) Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia. Proc Natl Acad Sci USA 97:2145–2150

    PubMed  CAS  Article  Google Scholar 

  115. Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, Marcucci G, Sondek J, Caligiuri MA, Der CJ (2001) Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. J Biol Chem 276:27145–27151

    PubMed  CAS  Article  Google Scholar 

  116. Mizuarai S, Yamanaka K, Kotani H (2006) Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells. Cancer Res 66:6319–6326

    PubMed  CAS  Article  Google Scholar 

  117. Dovas A, Couchman JR (2005) RhoGDI: multiple functions in the regulation of Rho family GTPase activities. Biochem J 390:1–9

    PubMed  CAS  Article  Google Scholar 

  118. Jones MB, Krutzsch H, Shu H, Zhao Y, Liotta LA, Kohn EC, Petricoin EF III (2002). Proteomic analysis and identification of new biomarkers and therapeutic targets for invasive ovarian cancer. Proteomics 2:76–84

    PubMed  CAS  Article  Google Scholar 

  119. Su LF, Knoblauch R, Garabedian MJ (2001) Rho GTPases as modulators of the estrogen receptor transcriptional response. J Biol Chem 276:3231–3237

    PubMed  CAS  Article  Google Scholar 

  120. Zhang Y, Zhang B (2006) D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness. Cancer Res 66:5592–5598

    PubMed  CAS  Article  Google Scholar 

  121. Theodorescu D, Sapinoso LM, Conaway MR, Oxford G, Hampton GM, Frierson HF Jr (2004) Reduced expression of metastasis suppressor RhoGDI2 is associated with decreased survival for patients with bladder cancer. Clin Cancer Res 10:3800–3806

    PubMed  CAS  Article  Google Scholar 

  122. Yuan BZ, Zhou X, Durkin ME, Zimonjic DB, Gumundsdottir K, Eyfjord JE, Thorgeirsson SS, Popescu NC (2003) DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity. Oncogene 22:445–450

    PubMed  CAS  Article  Google Scholar 

  123. Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY, Ng IO (2003) Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. J Biol Chem 278:10824–10830

    PubMed  CAS  Article  Google Scholar 

  124. Johnstone CN, Castellvi-Bel S, Chang LM, Bessa X, Nakagawa H, Harada H, Sung RK, Pique JM, Castells A, Rustgi AK (2004) ARHGAP8 is a novel member of the RHOGAP family related to ARHGAP1/CDC42GAP/p50RHOGAP: mutation and expression analyses in colorectal and breast cancers. Gene 336:59–71

    PubMed  CAS  Article  Google Scholar 

  125. Salh B, Marotta A, Wagey R, Sayed M, Pelech S (2002) Dysregulation of phosphatidylinositol 3-kinase and downstream effectors in human breast cancer. Int J Cancer 98:148–154

    PubMed  CAS  Article  Google Scholar 

  126. Vadlamudi RK, Adam L, Wang RA, Mandal M, Nguyen D, Sahin A, Chernoff J, Hung MC, Kumar R (2000) Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem 275:36238–36244

    PubMed  CAS  Article  Google Scholar 

  127. Qiu RG, Chen J, McCormick F, Symons M (1995) A role for Rho in Ras transformation. Proc Natl Acad Sci USA 92:11781–11785

    PubMed  CAS  Article  Google Scholar 

  128. Zohn IM, Campbell SL, Khosravi-Far R, Rossman KL, Der CJ (1998) Rho family proteins and Ras transformation: the RHOad less traveled gets congested. Oncogene 17:1415–1438

    PubMed  CAS  Article  Google Scholar 

  129. Joneson T, Bar-Sagi D (1999) Suppression of Ras-induced apoptosis by the Rac GTPase. Mol Cell Biol 19:5892–5901

    PubMed  CAS  Google Scholar 

  130. Sahai E, Olson MF, Marshall CJ (2001) Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. EMBO J 20:755–766

    PubMed  CAS  Article  Google Scholar 

  131. Liu AX, Rane N, Liu JP, Prendergast GC (2001) RhoB is dispensable for mouse development, but it modifies susceptibility to tumor formation as well as cell adhesion and growth factor signaling in transformed cells. Mol Cell Biol 21:6906–6912

    PubMed  CAS  Article  Google Scholar 

  132. Yu Q, Geng Y, Sicinski P (2001) Specific protection against breast cancers by cyclin D1 ablation. Nature 411:1017–1021

    PubMed  CAS  Article  Google Scholar 

  133. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142

    PubMed  CAS  Article  Google Scholar 

  134. Cowin P, Rowlands TM, Hatsell SJ (2005) Cadherins and catenins in breast cancer. Curr Opin Cell Biol 17:499–508

    PubMed  CAS  Article  Google Scholar 

  135. Lozano E, Betson M, Braga VM (2003) Tumor progression: Small GTPases and loss of cell–cell adhesion. Bioessays 25:452–463

    PubMed  CAS  Article  Google Scholar 

  136. Kovacs EM, Ali RG, McCormack AJ, Yap AS (2002) E-cadherin homophilic ligation directly signals through Rac and phosphatidylinositol 3-kinase to regulate adhesive contacts. J Biol Chem 277:6708–6718

    PubMed  CAS  Article  Google Scholar 

  137. Noren NK, Arthur WT, Burridge K (2003) Cadherin engagement inhibits RhoA via p190RhoGAP. J Biol Chem 278:13615–13618

    PubMed  CAS  Article  Google Scholar 

  138. Sander EE, van DS, ten Klooster JP, Reid T, van der Kammen RA, Michiels F, Collard JG (1998) Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell–cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J Cell Biol 143:1385–1398

    PubMed  CAS  Article  Google Scholar 

  139. Engers R, Springer E, Michiels F, Collard JG, Gabbert HE (2001) Rac affects invasion of human renal cell carcinomas by up-regulating tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 expression. J Biol Chem 276:41889–41897

    PubMed  CAS  Article  Google Scholar 

  140. Simpson KJ, Dugan AS, Mercurio AM (2004) Functional analysis of the contribution of RhoA and RhoC GTPases to invasive breast carcinoma. Cancer Res 64:8694–8701

    PubMed  CAS  Article  Google Scholar 

  141. Bellovin DI, Simpson KJ, Danilov T, Maynard E, Rimm DL, Oettgen P, Mercurio AM (2006) Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma. Oncogene 25:6959–6967

    PubMed  CAS  Article  Google Scholar 

  142. Clark EA, Golub TR, Lander ES, Hynes RO (2000) Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406:532–535

    PubMed  CAS  Article  Google Scholar 

  143. Hakem A, Sanchez-Sweatman O, You-Ten A, Duncan G, Wakeham A, Khokha R, Mak TW (2005) RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev 19:1974–1979

    PubMed  CAS  Article  Google Scholar 

  144. van Golen KL, Bao LW, Pan Q, Miller FR, Wu ZF, Merajver SD (2002) Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer. Clin Exp Metastasis 19:301–311

    PubMed  Article  Google Scholar 

  145. Hamelers IH, Olivo C, Mertens AE, Pegtel DM, van der Kammen RA, Sonnenberg A, Collard JG (2005) The Rac activator Tiam1 is required for (alpha)3(beta)1-mediated laminin-5 deposition, cell spreading, and cell migration. J Cell Biol 171:871–881

    PubMed  CAS  Article  Google Scholar 

  146. Tscharntke M, Pofahl R, Chrostek-Grashoff A, Smyth N, Niessen C, Niemann C, Hartwig B, Herzog V, Klein HW, Krieg T et al (2007) Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1. J Cell Sci 120:1480–1490

    PubMed  CAS  Article  Google Scholar 

  147. Mazieres J, Antonia T, Daste G, Muro-Cacho C, Berchery D, Tillement V, Pradines A, Sebti S, Favre G (2004) Loss of RhoB expression in human lung cancer progression. Clin Cancer Res 10:2742–2750

    PubMed  CAS  Article  Google Scholar 

  148. Adnane J, Muro-Cacho C, Mathews L, Sebti SM, Munoz-Antonia T (2002) Suppression of rho B expression in invasive carcinoma from head and neck cancer patients. Clin Cancer Res 8:2225–2232

    PubMed  CAS  Google Scholar 

  149. Liu N, Zhang G, Bi F, Pan Y, Xue Y, Shi Y, Yao L, Zhao L, Zheng Y, Fan D (2007) RhoC is essential for the metastasis of gastric cancer. J Mol Med 85:1149–1156

    PubMed  CAS  Article  Google Scholar 

  150. Suwa H, Ohshio G, Imamura T, Watanabe G, Arii S, Imamura M, Narumiya S, Hiai H, Fukumoto M (1998) Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br J Cancer 77:147–152

    PubMed  CAS  Google Scholar 

  151. Shikada Y, Yoshino I, Okamoto T, Fukuyama S, Kameyama T, Maehara Y (2003) Higher expression of RhoC is related to invasiveness in non-small cell lung carcinoma. Clin Cancer Res 9:5282–5286

    PubMed  CAS  Google Scholar 

  152. Kleer CG, Teknos TN, Islam M, Marcus B, Lee JS, Pan Q, Merajver SD (2006) RhoC GTPase expression as a potential marker of lymph node metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res 12:4485–4490

    PubMed  CAS  Article  Google Scholar 

  153. Liu SY, Yen CY, Yang SC, Chiang WF, Chang KW (2004) Overexpression of Rac-1 small GTPase binding protein in oral squamous cell carcinoma. J Oral Maxillofac Surg 62:702–707

    PubMed  Article  Google Scholar 

  154. Jiang WG, Watkins G, Lane J, Cunnick GH, Douglas-Jones A, Mokbel K, Mansel RE (2003) Prognostic value of rho GTPases and rho guanine nucleotide dissociation inhibitors in human breast cancers. Clin Cancer Res 9:6432–6440

    PubMed  CAS  Google Scholar 

  155. Zhang C, Zhou F, Li N, Shi S, Feng X, Chen Z, Hang J, Qiu B, Li B, Chang S et al (2007) Overexpression of RhoE has a prognostic value in non-small cell lung cancer. Ann Surg Oncol 14:2628–2635

    PubMed  Article  Google Scholar 

  156. Bektic J, Pfeil K, Berger AP, Ramoner R, Pelzer A, Schafer G, Kofler K, Bartsch G, Klocker H (2005) Small G-protein RhoE is underexpressed in prostate cancer and induces cell cycle arrest and apoptosis. Prostate 64:332–340

    PubMed  CAS  Article  Google Scholar 

  157. Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy DN, Molina JR, Fonseca R, Smyrk TC, Chari ST, Urrutia R, Billadeau DD (2005) Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis. Cancer Cell 7:39–49

    PubMed  CAS  Article  Google Scholar 

  158. Hornstein I, Pikarsky E, Groysman M, Amir G, Peylan-Ramu N, Katzav S (2003) The haematopoietic specific signal transducer Vav1 is expressed in a subset of human neuroblastomas. J Pathol 199:526–533

    PubMed  CAS  Article  Google Scholar 

  159. Ahn SJ, Chung KW, Lee RA, Park IA, Lee SH, Park DE, Noh DY (2003) Overexpression of betaPix-a in human breast cancer tissues. Cancer Lett 193:99–107

    PubMed  CAS  Article  Google Scholar 

  160. Tapper J, Kettunen E, El-Rifai W, Seppala M, Andersson LC, Knuutila S (2001) Changes in gene expression during progression of ovarian carcinoma. Cancer Genet Cytogenet 128:1–6

    PubMed  CAS  Article  Google Scholar 

  161. Wong CM, Lee JM, Ching YP, Jin DY, Ng IO (2003) Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer Res 63:7646–7651

    PubMed  CAS  Google Scholar 

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  1. Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Saskia I. J. Ellenbroek & John G. Collard

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Ellenbroek, S.I.J., Collard, J.G. Rho GTPases: functions and association with cancer. Clin Exp Metastasis 24, 657–672 (2007). https://doi.org/10.1007/s10585-007-9119-1

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Keywords

  • Rho GTPases
  • Rac
  • Tiam1
  • Signalling
  • Cell migration
  • Cell invasion
  • Cancer
  • Metastasis
  • Tumour progression